Ageing of the population due to increased life expectancy has brought with it a major increase in cognitive disorders associated with normal cerebral ageing and with pathological cerebral ageing occurring in the course of neurodegenerative diseases such as, for example, Alzheimer""s disease.
The majority of substances used today in treating cognitive disorders associated with ageing act by facilitating the central cholinergic systemsxe2x80x94either directly, as in the case of acetylcholinesterase inhibitors (tacrine, donepezil) and cholinergic agonists (nefiracetam), or indirectly, as in the case of nootropic agents (piracetam, pramiracetam) and cerebral vasodilators (vinpocetine).
Besides their cognitive properties, substances acting directly on the central cholinergic systems often have antalgic properties but also have hypothermic properties, which can be undesirable.
It has been therefore been especially valuable to synthesise new compounds that are capable of opposing the cognitive disorders associated with ageing and/or of improving cognitive processes and that can possess antalgic properties without having hypothermic activity.
4-Hydroxy- or 4-oxo-substituted 1-aza-2-alkyl-6-aryl-cycloalkanes and 1-aza-2-alkyl-6-aryl-cycloalkenes have already been described in the literature (J. Org. Chem. 1988, 53, 2426; Liebigs Ann. Chem. 1986, 11, 1823; Synlett 1993, 9, 657; Tet. Lett. 1998, 39(3/4), 217), but no pharmacological activity has been described for those compounds.
More specifically, the present invention relates to compounds of formula (I): 
wherein:
n represents 0 or 1,
R1 represents a hydrogen atom or an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)acyl group, a linear or branched (C1-C6)alkoxycarbonyl group, an aryl-(C1-C6)-alkoxycarbonyl group in which the alkoxy moiety is linear or branched, or a trifluoro-acetyl group,
R2 represents a linear or branched (C1-C6)alkyl group,
X represents an oxygen or chlorine atom or a group OR3, SR4 or NOR5,
R3 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)acyl group, a linear or branched (C1-C6)alkoxycarbonyl group or an aryl-(C1-C6)alkoxycarbonyl group in which the alkoxy moiety is linear or branched,
R4 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group or an aryl group,
R5 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group optionally substituted by one or more identical or different groups selected from hydroxy, amino (optionally substituted by one or two linear or branched (C1-C6)alkyl groups) and linear or branched (C1-C6)alkoxy,
 represents a single or double bond, it being understood that the valency of the atoms is respected,
Ar represents an aryl group or a heteroaryl group,
their isomers and addition salts thereof with a pharmaceutically acceptable acid,
with the proviso that the compounds of formula (I) are other than:
6-methyl-2-phenyl-2,3-dihydro-4-pyridinone,
2-methyl-6-phenyl-4-piperidinone,
N-benzyl-2-(Rxe2x80x22)-6-phenyl-4-piperidinones wherein Rxe2x80x22 represents a methyl, ethyl, propyl or isopropyl group,
and 2-(Rxe2x80x32)-6-phenyl-4-piperidinols wherein Rxe2x80x32 represents an isopropyl or butyl group.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, benzenesulphonic acid, camphoric acid etc.
An aryl group is understood to be phenyl, biphenylyl, naphthyl or tetrahydronaphthyl, each of those groups being optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, trihalomethyl and amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups).
A heteroaryl group is understood to be an aromatic, mono- or bi-cyclic, 5- to 12-membered group containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, it being understood that the heteroaryl group may be optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, trihalomethyl and amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups). Among the heteroaryl groups there may be mentioned, without implying any limitation, thienyl, pyridyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl groups.
Preferred compounds of formula (I) are those wherein n represents 0.
The group X as defined for formula (I) is preferably an oxygen atom or a group OR3 wherein R3 represents a hydrogen atom.
The group R1 as defined for formula (I) is preferably a hydrogen atom.
The term xe2x80x9carylxe2x80x9d used in respect of the group Ar as defined for formula (I) is preferably an optionally substituted phenyl group.
The term xe2x80x9cheteroarylxe2x80x9d used in respect of the group Ar as defined for formula (I) is preferably an optionally substituted thienyl group or an optionally substituted pyridyl group.
The invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that a compound of formula (II): 
wherein Ar and n are as defined for formula (I),
is reacted with thionyl chloride to yield the corresponding acid chloride, which is reacted with a compound of formula (III): 
wherein R2 is as defined for formula (I),
in the presence of samarium triiodide,
to yield, after deprotection by an acid HA, the compound of formula (IV): 
wherein Ar, n and R2 are as defined hereinbefore and HA represents a proton donor acid,
which compound of formula (IV) is then reacted in a basic medium to yield the compound of formula (Ia), a particular case of the compounds of formula (I): 
wherein Ar, n and R2 are as defined hereinbefore,
which compound of formula (Ia) is condensed, if desired, with a compound of formula Rxe2x80x21xe2x80x94Y, wherein Rxe2x80x21, represents an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)acyl group, a linear or branched (C1-C6)alkoxycarbonyl group, an aryl-(C1-C6)alkoxycarbonyl group in which the alkoxy moiety is linear or branched, or a trifluoroacetyl group and Y represents a leaving group, to yield the compound of formula (Ib), a particular case of the compounds of formula (I): 
wherein Ar, n, Rxe2x80x21 and R2 are as defined hereinbefore,
which compound of formula (Ia) or (Ib) is converted, if desired,
either by partial reduction with the aid of an appropriate reducing agent, followed, if desired, by alkylation, acylation or esterification of the hydroxy function to yield the compound of formula (Ic), a particular case of the compounds of formula (I): 
xe2x80x83wherein Ar, n and R2 are as defined hereinbefore and R1 and R3 are as defined for formula (I),
or by complete reduction with the aid of an appropriate reducing agent to yield the compound of formula (Id), a particular case of the compounds of formula (I): 
xe2x80x83wherein Ar, n, R1 and R2 are as defined hereinbefore,
which compound of formula (Id) is reacted, if desired,
either with a compound of formula Rxe2x80x23xe2x80x94Y, wherein Rxe2x80x23 represents a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)acyl group, a linear or branched (C1-C6)alkoxycarbonyl group or an aryl-(C1-C6)alkoxycarbonyl group in which the alkoxy moiety is linear or branched and Y represents a leaving group, to yield the compound of formula (Ie), a particular case of the compounds of formula (I): 
xe2x80x83wherein Ar, n, R1, R2 and Rxe2x80x23 are as defined hereinbefore,
or in an oxidation reaction using an appropriate oxidising agent, to form an oxo group, yielding the compound of formula (If), a particular case of the compounds of formula (I): 
xe2x80x83wherein Ar, n, R1 and R2 are as defined hereinbefore,
which compounds of formula (Ia), (Ib) or (If) are reacted, if desired,
either with a chlorinating agent such as, for example, thionyl chloride to yield the compound of formula (Ig), a particular case of the compounds of formula (I): 
xe2x80x83wherein Ar, n, R1 and R2 are as defined hereinbefore and  is as defined for formula (I),
which is reacted, if desired, with a compound of formula HSR4, wherein R4 is as defined for formula (I), to yield the compound of formula (Ih), a particular case of the compounds of formula (I): 
xe2x80x83wherein Ar, n, R1, R2, R4 and  are as defined for formula (I),
or with a compound of formula H2N-OR5, wherein R5 is as defined for formula (I), to yield the compound of formula (Ii), a particular case of the compounds of formula (I): 
xe2x80x83wherein Ar, n, R1, R2, R5 and  are as defined hereinbefore, the compounds of formulae (I/a), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) and (Ii) constituting the totality of the compounds of formula (I), which are purified, if necessary, according to a conventional purification technique, are separated, if desired, into their isomers according to a conventional separation technique and are converted, if desired, into their addition salts with a pharmaceutically acceptable acid.
The compound of formula (II) is obtained by starting from the compound of formula (VI):
Arxe2x80x94CHOxe2x80x83xe2x80x83(VI)
wherein Ar is as defined hereinbefore, which is converted into a compound of formula (VII): 
wherein Ar and n are as defined hereinbefore,
when n is 0, according to the procedure described by W. M. Rodionow and E. Th. Malewinskaya in Ber. 1926, 59, 2952 and T. B. Johnson, J. E. Livak in J. Am. Chem. Soc. 1936, 58, 299
when n is 1, according to the procedure described by Keberle in Patent Specification CH 449046,
which compound of formula (VII) is optionally resolved (when it is desired to obtain the compound of formula (I) in its enantiomerically pure form) according to a conventional resolution technique before being converted into a compound of formula (II) by reaction with trifluoroacetic anhydride.
In addition to the fact that the compounds of the present invention are new, they exhibit properties facilitating cognitive processes and antalgic properties, rendering them of use in the treatment of cognitive deficiencies associated with cerebral ageing and with neurodegenerative pathologies, such as Alzheimer""s disease, Parkinson""s disease, Pick""s disease, Korsakoffs disease and frontal lobe and subcortical dementias and in the treatment of pain.
The invention relates also to pharmaceutical compositions comprising as active ingredient a compound of formula (I) together with one or more appropriate, inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous or subcutaneous) and nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions etc.
The dosage used can be adapted to the nature and the severity of the disorder, the administration route and the age and weight of the patient. The dosage varies from 1 to 500 mg per day in one or more administrations.
The following Examples illustrate the invention without limiting it in any way. DMSO is to be understood as meaning dimethylsulfoxide.
A compound having the relative configuration (2R*, 4S*, 6R*) is understood to be a racemic mixture of the compounds having the absolute configurations (2R, 4S, 6R) and (2S, 4R, 6S).
The starting materials used are products that are known or prepared according to known procedures.
The structures of the compounds described in the Examples were determined according to customary spectrophotometric techniques (infrared, NMR, mass spectrometry).